Medical Hypotheses 109 (2017) 181–183

Contents lists available at ScienceDirect

Medical Hypotheses

journal homepage: www.elsevier.com/locate/mehy

Transcutaneous neuromuscular electrical stimulation may be beneficial in MARK the treatment of premature

Ilan Gruenwalda, Ege Can Serefoglub, Tal Gollanc, Shmuel Springerd, Gideon Meiryc, Boaz Appela, ⁎ Arik Shechtera,e, a Neurourology Unit, Rambam Healthcare Campus, Haifa, Israel b UroKlinik, Istanbul, Turkey c Virility, Israel d Physical Therapy Department, Faculty of Health Sciences Ariel University, Israel e Department of Family Medicine, Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Clalit Health Services, Haifa, Israel

ABSTRACT

Approximately 20–30% of sexually active men suffer from Premature Ejaculation (PE), but the pathophysiology still remains unclear and the current available treatments for PE are unsatisfying. Considering the role of rhythmic bulbospongiosus and ischiocavernosus Muscles contractions on the ejaculatory reflex, we hypothesize that weakening this muscles via inhibiting it’s contractions by Application of Neuromuscular Electrical Stimulation prior to the planned sexual activity, may have a beneficial effect in the treatment of PE. Using miniaturized perineal on-demand stimulation device, in a home setting during sexual intercourse may become the first line of treatment for PE.

Introduction result of epithelial secretion and smooth muscle cell contraction [7]. All of the organs contributing to emission phase receive a dense autonomic Premature ejaculation (PE) is a very common and disturbing sexual innervation composed of both sympathetic and parasympathetic axons, dysfunction in men, associated with detrimental psychological, physical which are mainly derived from the pelvic plexus. Epididymis, vas de- and social effects. Approximately 20–30% of sexually active men suffer ferens, seminal vesicles, gland, prostatic and bladder from PE (Porst et al., 2007; [1–3]). Although this dysfunction has been neck are all involved in the emission phase [6]. widely investigated, its pathophysiology still remains unclear. Today, Expulsion is a spinal cord reflex, which causes the ejection of sperm there is only one oral compound, which has been specifically developed from the posterior urethra to the meatus. During this phase, smooth for the pharmaceutical treatment of PE, Dapoxetine. Although it has muscle bundles contract in the bladder neck to prevent backflow of been approved by the European Medical Agency (EMEA), Dapoxetine semen into the bladder, and the pelvic floor muscles, with bulbos- has not been approved by the U.S. Food and Drug Administration pongiosus and ischiocavernosus muscles playing major functional roles, (FDA), due to its controversial efficacy and safety (Mondaini et al., display significant rhythmic contractions to propel semen distally, 2013; [4, 5]). Therefore, the treatment of PE continues to be a major throughout the bulbar and penile urethra towards the meatus [8,9]. area of medical research. Definition and pathophysiology of PE Physiology of ejaculation The exact definition, epidemiology, classification and pathophy- From the physiologic point of view, ejaculation has two phases: siology of PE have been dispersed over time [10]. In the recent years, emission and expulsion, which involve several pelvi-perineal anato- there has been some progress in PE research, which resulted in a better mical structures. After a sufficient erotic stimulus, a tight coordination understanding and study of this prevalent condition [11]. Several of sympathetic, parasympathetic and somatic divisions of the nervous professional organizations such as the American Psychiatric Association system is necessary for a normal ante grade ejaculation [6]. (APA) and the International Society for Sexual Medicine (ISSM) have Emission is the ejection of semen into the posterior urethra, as a revised their PE definitions considering the recent evidence pertaining

⁎ Corresponding author. E-mail address: [email protected] (A. Shechter). http://dx.doi.org/10.1016/j.mehy.2017.10.008 Received 20 July 2017; Accepted 7 October 2017 0306-9877/ © 2017 Published by Elsevier Ltd. I. Gruenwald et al. Medical Hypotheses 109 (2017) 181–183 to PE [12,13]. Considering the key elements (time, control and distress) Hypothesis in these evidence-based definitions, PE can be defined as: 1) An eja- culation that occurs at less than 1 min from vaginal penetration (pri- As ejaculation involves rapid stereotyped rhythmic contractions of mary or lifelong PE) or less than 3 min (secondary or acquired PE); and the bulbospongiosus and ischiocavernosus muscles, inhibiting this type 2) ejaculation that cannot be postponed in nearly all attempts with of contractions may have a beneficial effect in the treatment of PE. vaginal penetration; and 3) PE inflicts personal distress with negative When a muscle is continuously stimulated the successive contractions consequences such as avoidance of sexual relations [13]. fuse together resulting in inability of muscle relaxation. Application of It is well accepted in modern sexology, that within reasonable NMES to these muscles prior to the planned sexual activity may keep limits, if a patient experiences dissatisfaction and distress as a result of them in a sub-tetanic sustained contraction for several minutes, which inability to control the timing of , he is eligible to medical as- may inhibit the natural rhythmic muscle contractions, which is neces- sistance, regardless of his objective latency time. sary for the completion of the ejaculatory process. This intervention The mechanisms, which play role in the pathophysiology of PE, may significantly increase the time to ejaculation in patients with PE. have not yet been completely elucidated. Hyposensitivity and/or hy- However, there are some limitations of our hypothesis. Though the persensitivity of the central serotonin receptors [14], genetic factors carry-over effect (i.e., increased ejaculatory latency time) of NMES to [15], endocrinologic disruptions [16] and some urologic conditions improve the contractile strength of these muscles has been reported [17,18] may be responsible for the hyperactivity of the ejaculation after a repetitive treatment [33], the immediate on-demand effect of reflex. In addition to these organic disorders, psychological problems NMES during sexual intercourse has not been demonstrated yet. Thus, a (e.g. performance anxiety, relationship problems and etc.) may cause well-designed clinical study is necessary to establish this effect. Another acquired PE [19] by activating the sympathetic nervous system and important issue of such study should be to reject the undesirable causing reduced ejaculatory threshold [20]. probability of anejaculation which might be characterized by the ab- sence of ejaculation due to the spastic contraction of these muscles. Furthermore, a technical factor that needs to be considered is the ability Treatment of premature ejaculation of the subject to accurately position the electrodes in the correct place in the in order to achieve the desired outcome of delaying the In the past, the origin of PE was attributed mainly to psychological ejaculation. Hence, future studies should evaluate the effectiveness of factors; nevertheless, possible neurobiological aetiologies were recently this on demand treatment in comparison with other commonly used proposed [21]. These advancements revolutionized the PE treatment treatments. and currently pharmacotherapy is considered as the most effective We believe that the new on-demand application of NMES on the treatment in PE [22]. Until recently only chronic selective serotonin perineum skin may be a viable, efficient and safe treatment option for reuptake inhibitors (SSRIs) confirmed their role as first-line agents with PE, if the efficacy of this therapy will be proven by future studies, we their consistent efficacy in delaying ejaculation [23]. However, only suggest to develop a transcutaneous electrical stimulation miniature Dapoxetine (Priligy, Menarini, Italy), which is a short acting SSRI, has device for the treatment of premature ejaculation. been approved for the treatment of PE [24]. Unfortunately, recent post- marketing studies demonstrated that discontinuation rate of Dapox- Conflict of interests etine is very high [4,25] due to its limited efficacy and side effects [26]. Therefore, several new compounds are being investigated as an alter- Gruenwald Ilan – consultant for Virility Medical, a company that native for PE treatment. intends to develop a device based on this hypothesis. Considering the role of rhythmic bulbospongiosus muscle contrac- Ege Can Serefoglu – consultant for Virility Medical, a company that tions on the ejaculatory reflex, Serefoglu and Silay hypothesized that intends to develop a device based on this hypothesis. weakening this muscle via botulinum toxin injections may delay the Tal Gollan – CEO of Virility Medical, a company that intends to time of ejaculation [27]. In an animal study, botulinum-A toxin injec- develop a device based on this hypothesis. tion into the bulbospongiosus muscle is shown to be effective in ex- Shmuel Springer – consultant for Virility Medical, a company that tending the ejaculatory latency without affecting the ability to engage intends to develop a device based on this hypothesis. in sexual activity or achieve ejaculation [28]. Although clinical studies Gideon Meiry – consultant for Virility Medical, a company that in- which demonstrate the efficacy and safety of this treatment modality in tends to develop a device based on this hypothesis. men with PE are being conducted, their results have not been published Boaz Appel – Non. yet (ClinicalTrials.gov Identifier: NCT01917006). Arik Shechter – consultant for Virility Medical, a company that in- tends to develop a device based on this hypothesis. Transcutaneous neuromuscular electrical stimulation Appendix A. Supplementary data Neuromuscular electrical stimulation (NMES) involves the applica- tion of a series of intermittent stimuli to superficial muscles, with the Supplementary data associated with this article can be found, in the main objective to trigger muscle contractions due to the activation of online version, at http://dx.doi.org/10.1016/j.mehy.2017.10.008. the intramuscular branches [29]. Transcutaneous NMES is a common and well-recognized treatment to improve muscle function References [29]. Eriksen and Mjølnerød [24] defined pelvic floor NMES as the acti- [1] Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J. The Premature vation of the afferents, which results in contractions of Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and – fl ffi professional help-seeking. Eur Urol 2007;51:816 23. discussion 824. the smooth and striated muscles in the pelvic oor. The e cacy of [2] Serefoglu EC, Yaman O, Cayan S. Prevalence of the complaint of ejaculating pre- pelvic floor muscle training using transcutaneous NMES in many ur- maturely and the four premature ejaculation syndromes: results from the Turkish ological problems (e.g. lower urinary tract symptoms, urinary incon- society of andrology sexual health survey. J Sex Med 2011;8:540–8. [3] Waldinger MD, Schweitzer DH. Changing paradigms from a historical DSM-III and tinence, erectile dysfunction and premature ejaculation) has been de- DSM-IV view toward an evidence-based definition of premature ejaculation. Part monstrated [30–32]. These studies revealed that contraction of the II–proposals for DSM-V and ICD-11. J Sex Med 2006;3:693–705. male pelvic floor muscles (i.e., bulbospongiosus and ischiocavernosus) [4] Mondaini N, Fusco F, Cai T, Benemei S, Mirone V, Bartoletti R. Dapoxetine treat- “ ” via NMES can be safely performed for several minutes, with good ment in patients with lifelong premature ejaculation: the reasons of a Waterloo Urology 2013;82:620–4. perception and without discomfort [27,28].

182 I. Gruenwald et al. Medical Hypotheses 109 (2017) 181–183

[5] Jern P, Johansson A, Piha J, Westberg L, Santtila P. Antidepressant treatment of [20] Janssen PK, Bakker SC, Rethelyi J. Serotonin transporter promoter region (5- premature ejaculation: discontinuation rates and prevalence of side effects for da- HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time poxetine and paroxetine in a naturalistic setting. Int J Impot Res 2014. in Dutch men with lifelong premature ejaculation. J Sex Med 2009;6:276–84. [6] Giuliano F, Clement P. Physiology of ejaculation: emphasis on serotonergic control. [21] Waldinger MD. The neurobiological approach to premature ejaculation. J Urol Eur Urol 2005;48:408–17. 2002;168:2359–67. [7] Amelar RD, Hotchkiss RS. The split ejaculate: its use in the management of male [22] McMahon CG, Porst H. Oral agents for the treatment of premature ejaculation: infertility. Fertil Steril 1965;16:46–60. review of efficacy and safety in the context of the recent international society for [8] Gerstenberg TC, Levin RJ, Wagner G. and ejaculation in man. Assessment sexual medicine criteria for lifelong premature ejaculation. J Sex Med of the electromyographic activity of the bulbocavernosus and ischiocavernosus 2011;8:2707–25. muscles. Br J Urol 1990;65:395–402. [23] Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of metho- [9] Shafik A. Response of the urethral and intracorporeal pressures to cavernosus dological design for the interpretation of efficacy of drug treatment of premature muscle stimulation: role of the muscles in erection and ejaculation. Urology ejaculation: a systematic review and meta-analysis. Int J Impot Res 1995;46:85–8. 2004;16:369–81. [10] Saitz TR, Serefoglu EC. Advances in understanding and treating premature ejacu- [24] Sangkum P, Badr R, Serefoglu EC, Hellstrom WJ. Dapoxetine and the treatment of lation. Nature reviews. Urology 2015;12:629–40. premature ejaculation. Transl Androl Urol 2013;2:301–11. [11] Althof SE, McMahon CG, Waldinger MD, et al. An update of the international so- [25] Park HJ, Park NC, Kim TN, Baek SR, Lee KM, Choe S. Discontinuation of dapoxetine ciety of sexual medicine's guidelines for the diagnosis and treatment of premature treatment in patients with premature ejaculation: a 2-Year prospective observa- ejaculation (PE). J Sex Med 2014;11:1392–422. tional study. Sex Med 2017;5:e99–105. [12] American Psychiatric Association. The Diagnostic and Statistical Manual of Mental [26] Cooper K, Martyn-St James M, Kaltenthaler E, Dickinson K, Cantrell A. Disorders. Fifth Edition Washington, DC: American Psychiatric Association; 2013. Interventions to treat premature ejaculation: a systematic review short report. [13] Serefoglu EC, McMahon CG, Waldinger MD, et al. An evidence-based unified defi- Health Technol Assess 2015;19:1–180. Winchester, England, v-vi. nition of lifelong and acquired premature ejaculation: report of the second inter- [27] Serefoglu EC, Silay MS. Botulinum toxin-A injection may be beneficial in the national society for sexual medicine Ad Hoc committee for the definition of pre- treatment of life-long premature ejaculation. Med Hypotheses 2010;74:83–4. mature ejaculation. J Sex Med 2014;11:1423–41. [28] Serefoglu EC, Hawley WR, Lasker GF. Effect of botulinum-A toxin injection into [14] Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature ejacula- bulbospongiosus muscle on ejaculation latency in male rats. J Sex Med tion and serotonergic antidepressants-induced delayed ejaculation: the involvement 2014;11:1657–63. of the serotonergic system. Behav Brain Res 1998;92:111–8. [29] Herzig D, Maffiuletti NA, Eser P. The Application of neuromuscular electrical sti- [15] Waldinger MD, Quinn P, Dilleen M, Mundayat R, Schweitzer DH, Boolell M. A mulation training in various non-neurologic patient populations: a narrative review. multinational population survey of intravaginal ejaculation latency time. J Sex Med PMR: J Inj funct Rehabil 2015;7:1167–78. 2005;2:492–7. [30] McClurg D, Ashe RG, Lowe-Strong AS. Neuromuscular electrical stimulation and the [16] Waldinger MD. Ejaculatio praecox, erectio praecox, and detumescentia praecox as treatment of lower urinary tract dysfunction in multiple sclerosis—a double blind, symptoms of a hypertonic state in lifelong premature ejaculation: a new hypothesis. placebo controlled, randomised clinical trial. Neurourol Urodyn 2008;27:231–7. Pharmacol Biochem Behav 2014;121:189–94. [31] Eder SE. Evaluation of the EmbaGYN pelvic floor muscle stimulator in addition to [17] Lee JH, Lee SW. Relationship between premature ejaculation and chronic prosta- Kegel exercises for the treatment of female stress urinary incontinence. a pro- titis/chronic pelvic pain syndrome. J Sex Med 2015;12:697–704. spective, open-label, multicenter, single-arm study. Women's health [18] Gao J, Xu C, Liang C, et al. Relationships between intravaginal ejaculatory latency 2014;10:17–27. London, England. time and national institutes of health-chronic prostatitis symptom index in the four [32] Lavoisier P, Roy P, Dantony E, Watrelot A, Ruggeri J, Dumoulin S. Pelvic-floor types of premature ejaculation syndromes: a large observational study in China. J muscle rehabilitation in erectile dysfunction and premature ejaculation. Phys Ther Sex Med 2014;11:3093–101. 2014;94:1731–43. [19] Hartmann U, Schedlowski M, Kruger TH. Cognitive and partner-related factors in [33] Pastore AL, Palleschi G, Fuschi A, et al. Pelvic floor muscle rehabilitation for pa- rapid ejaculation: di fferences between dysfunctional and functional men. World J tients with lifelong premature ejaculation: a novel therapeutic approach. Ther Adv Urol 2005;23:93–101. Urol 2014;6:83–8.

183